The identification of new pharmacophores is of paramount biomedical importance and natural products have recently been regaining attention for this endeavor. Koehn, F. E.; Carter, G. T. Nat. Rev. Drug Discov. 2005, 4, 206-220; Paterson, I.; Anderson, E. A. Science 2005, 310, 451-453. This renaissance is closely tied to the successful exploitation of the marine environment which harbors unmatched biodiversity that is presumably concomitant with chemical diversity. Fenical, W.; Jensen, P. R. Nat. Chem. Biol. 2006, 2, 666-673. In particular, marine cyanobacteria are prolific producers of bioactive secondary metabolites (Gerwick, W. H.; Tan, L. T.; Sitachitta, N. Alkaloids Chem. Biol. 2001, 57, 75-184), many of which are modified peptides or peptide-polyketide hybrids with promising antitumor activities, such as dolastatin 10 (Luesch, H.; Moore, R. E.; Paul, V. J.; Mooberry, S. L.; Corbett, T. H. J. Nat. Prod. 2001, 64, 907-910), curacin A (Gerwick, W. H.; Proteau, P. J.; Nagle, D. G.; Hamel, E.; Blokhin, A.; Slate, D. L. J. Org. Chem. 1994, 59, 1243-1245; Verdier-Pinard, P.; Lai, J.-Y.; Yoo, H.-D.; Yu, J.; Marquez, B.; Nagle, D. G.; Nambu, M.; White, J. D.; Falck, J. R.; Gerwick, W. H.; Day, B. W.; Hamel, E. Mol. Pharmacol. 1998, 53, 62-76), and apratoxin A (Luesch, H.; Yoshida, W. Y.; Moore, R. E.; Paul, V. J.; Corbett, T. H. J. Am. Chem. Soc. 2001, 123, 5418-5423; Luesch, H.; Chanda, S. K.; Raya, M. R.; DeJesus, P. D.; Orth, A. P.; Walker, J. R.; Izpisúa Belmonte, J. C.; Schultz, P. G. Nat. Chem. Biol. 2006, 2, 158-167). As a result of ongoing investigations to identify new drug leads from cyanobacteria in Florida, described here is the structure determination and preliminary biological characterization of a marine cyanobacterial metabolite with novel chemical scaffold and antiproliferative activity. These findings provide new alternatives to address unmet needs in the treatment of proliferation diseases and disorders.
Described here is the cytotoxicity-guided isolation of a new cytotoxic depsipeptide, grassypeptolide (1), from an extract of L. confervoides collected in the Florida Keys. This cyanobacterium was of interest because it inhibited settlement of coral larvae (Porites asteroides) and reduced survival of coral recruits.1 Grassypeptolide (1) contains some unusual residues, such as the β-amino acid 2-methyl-3-aminobutyric acid (Maba, C1-5) and 2-aminobutyric acid (Aba, C20-23). Until now, the Aba unit had precedence only in sponge metabolites,2 whereas the Maba unit was found in one other cyanobacterial compound, guineamide B.3 Additionally, compound 1 consists of an unusually high number of D-amino acid units. The tandem thiazoline rings flanking the D-Aba derived moiety are reminiscent of the lissoclinamides and the patellamides, which are cyclic peptides containing up to four cysteine- and serine-derived cyclocondensation products and which tend to contain D-amino acids.4,5 Lissoclinamide 7,4 closest related to 1 and the most cytotoxic of the series, has two thiazoline rings with the same arrangement and stereoconfiguration as 1, yet the macrocycle is only 21-membered in Lissoclinamide 7 as opposed to 31-membered in 1. Although both the lissoclinamides and the patellamides were originally isolated from the ascidian Lissoclinum patella, the biosynthetic gene cluster for patellamides A and C was recently found in the obligate symbiotic cyanobacterium Prochloron didemni.5 Remarkably, these compounds are synthesized ribosomally, rather than by nonribosomal peptide synthetases (NRPS).5 Grassypeptolide (1) is the first reported compound with tandem thiazoline rings in the depicted arrangement to be produced by an independently living cyanobacterium. 1Kuffner, I. B.; Walters, L. J.; Becerro, M. A.; Paul, V. J.; Ritson-Williams, R.; Beach, K. S. Mar. Ecol. Prog. Ser. 2006, 323, 107-117.2(a) Fusetani, N.; Sugawara, T.; Matsunaga, S.; Hirota, H. J. Am. Chem. Soc. 1991, 113, 7811-7812. (b) Kobayashi, J.; Itagaki, F.; Shigemori, H.; Ishibashi, M.; Takahashi, K.; Ogura, M.; Nagasawa, S.; Nakamura, T.; Hirota, H.; Ohta, T.; Nozoe, S. J. Am. Chem. Soc. 1991, 113, 7812-7813. (c) Nakao, Y.; Fujita, M.; Warabi, K.; Matsunaga, S.; Fusetani, N. J. Am. Chem. Soc. 2000, 122, 10462-10463.3Tan, L. T.; Sitachitta, N.; Gerwick, W. H. J. Nat. Prod. 2003, 66, 764-771.4Wipf, P.; Fritch, P. C.; Geib, S. J.; Sefler, A. M. J. Am. Chem. Soc. 1998, 120, 4105-4112.5(a) Schmidt, E. W.; Nelson, J. T.; Rasko, D. A.; Sudek, S.; Eisen, J. A.; Haygood, M. G.; Ravel, J. Proc. Natl. Acad. Sci. USA 2005, 102, 7315-7320. (b) Long, P. F.; Dunlap, W. C.; Battershill, C. N.; Jaspars, M. ChemBioChem 2005, 6, 1760-1765.